The Genom of Homo sapiens.pdf

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QUALITY ASSESSMENT OF FINISHED SEQUENCE 35Figure 3. False join, resolvable through pairedendexamination.consensus on the other side of the gap. Although there isonly a single high-quality read that bridges the gap, theclone meets the existing finishing criteria because the extentof the single subclone read is less than 100 bp. Onmany occasions, we found that the single subclone read“closed” the gap merely due to the fact that the sequencingreaction skipped the hairpin, deleting portions of sequenceto bridge the gap, or was a reaction performed ona deleted template. This is not identifiable through pairedend-link examination, as usually the sequence missing isnot enough to skew the size distribution of the pairedends. In these cases, another subclone should always besampled to confirm that the join across the difficult regionis accurate. As a general rule, single subclone regions of
36 SCHMUTZ ET AL.compared. Some of these algorithms are designed to addressa single allelic copy WGS and do not work on thepolymorphic data sets. In addition, the algorithms vary intheir ability to resolve repeats based on paired end links.The resulting assemblies of vertebrates are large, and themetrics for comparing them have yet to be established.We need a standard polymorphic and a standard inbredWGS data set, along with finished genomes for both, tobe able to compare the effectiveness and accuracy of theWGS assembly. As we venture farther away from humansequence in evolutionary terms, we will uncover new anddifficult problems in other species, which will add to theproblem of defining the genome quality. The sequencecoverage levels for published assemblies for nonhumanWGS data sets vary from 1.5x for the poodle to 10.2x formosquito, with Fugu falling in between at 5.6x. The coveragelevel is likely to vary for most WGS organisms dueto funding pressures and the desirability of completenessfor the genome. The variation in sequence coverage, togetherwith cloning bias and repeated sequences, combineto cause significant issues with evaluating a finalWGS product. Furthermore, the finishing rules in placefor human cannot be applied to the resulting assemblies.This includes our notion of completeness, as the WGS assemblersmust through necessity discard many sequencetraces that cannot be placed due to repeats or that are contradictoryto already assembled contigs. In addition, becausecontamination is common in the large data sets,many reads will not be placed in the finished product.One approach for quality control and assessment for theWGS data sets is to finish a randomly selected set of largeinsertclones to a high degree and compare the resultingconsensus sequence to the WGS assembly. The finishedclones will both provide a training set of sequence for theassembly process and serve to verify a portion of the WGSconsensus. One percent or more of the total organismshould be finished in a clone-based approach to ensure thequality and accuracy of the draft assembly.CONCLUSIONSWith our evaluation of the finished human genome sequence,we determined that the majority of the humangenome sequence exceeded the accuracy standards; however,there are improvements that can be made to the finishedgenome and to the current finishing standards. Thefinished genome of Drosophila has had its third finishedrelease (Celniker et al. 2002), and the human genome hasalready had one new assembly since the April finisheddate. We expect that improvements to the final humangenome will continue as new techniques are developedwhich can address the serious remaining issues of segmentalduplications and sequences that are unclonable inexisting vector systems. The data producers face the difficultchallenge of maintaining the finished sequence qualitystandards used for the evaluation of the human genomesequence as many more genomic sequences, each havingtheir own unique experimental problems to overcome, areproduced and finished. As it becomes even faster and easierto produce draft genomes, we must, as a community,address the concerns of sequence accuracy of the WGS assembliesand provide benchmarks of acceptable qualityfor these genomic sequences, given the intended scientificuses of these data sets. Regardless, once finishing standardsare defined and agreed upon, it would be wise to integratea quality assessment strategy into the productionprocess, so that global statements of genome quality canbe made for each future genome project.ACKNOWLEDGMENTWe thank James Retterer for the illustrations includedin this manuscript.REFERENCESAdams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., GalleR.F., George R.A., Lewis S.E., Richards S., Ashburner M., HendersonS.N., Sutton G.G., Wortman J.R., Yandell M.D., ZhangQ., Chen L.X., Brandon R.C., Rogers Y.H., Blazej R.G.,Champe M., and Pfeiffer B.D., et al. 2000. The genome sequenceof Drosophila melanogaster. Science 287: 2185.Aparicio S., Chapman J., Stupka E., Putnam N., Chia J.M., DehalP., Christoffels A., Rash S., Hoon S., Smit A., GelpkeM.D., Roach J., Oh T., Ho I.Y., Wong M., Detter C., VerhoefF., Predki P., Tay A., Lucas S., Richardson P., Smith S.F.,Clark M.S., Edwards Y.J., and Doggett N., et al. 2002.Whole-genome shotgun assembly and analysis of the genomeof Fugu rubripes. Science 297: 1301.Batzoglou S., Jaffe D.B., Stanley K., Butler J., Gnerre S.,Mauceli E., Berger B., Mesirov J.P., and Lander E.S. 2002.ARACHNE: A whole-genome shotgun assembler. GenomeRes. 12: 177.Celniker S.E., Wheeler D.A., Kronmiller B., Carlson J.W.,Halpern A., Patel S., Adams M., Champe M., Dugan S.P., FriseE., Hodgson A., George R.A., Hoskins R.A., Laverty T.,Muzny D.M., Nelson C.R., Pacleb J.M., Park S., Pfeiffer B.D.,Richards S., Sodergren E.J., Svirskas R., Tabor P.E., Wan K.,and Stapleton M., et al. 2002. Finishing a whole-genome shotgun:Release 3 of the Drosophila melanogaster euchromaticgenome sequence. Genome Biol. 3: RESEARCH0079.Dehal P., Satou Y., Campbell R.K., Chapman J., Degnan B., DeTomaso A., Davidson B., Di Gregorio A., Gelpke M., GoodsteinD.M., Harafuji N., Hastings K.E., Ho I., Hotta K., HuangW., Kawashima T., Lemaire P., Martinez D., MeinertzhagenI.A., Necula S., Nonaka M., Putnam N., Rash S., Saiga H.,and Satake M., et al. 2002. The Draft genome of Ciona intestinalis:Insights into chordate and vertebrate origins. Science298: 2157.Ewing B. and Green P. 1998. Base-calling of automated sequencingtraces using Phred. II. Error probabilities. GenomeRes. 8: 186.Ewing B., Hiller L., Wendl M., and Green P. 1998. Base-callingof automated sequence traces using Phred. I. Accuracy assessment.Genome Res. 8: 175.Felsenfeld A., Peterson J., Schloss J., and Guyer M. 1999. Assessingthe quality of the DNA sequence from the humangenome project. Genome Res. 9: 1.Gordon D., Abajian C., and Green P. 1998. Consed: A graphicaltool for sequence finishing. Genome Res. 8: 195.Green P. 2002. Whole-genome disassembly. Proc. Natl. Acad.Sci. 99: 4143.Holt R.A., Subramanian G.M., Halpern A., Sutton G.G., CharlabR., Nusskern D.R., Wincker P., Clark A.G., Ribeiro J.M.,Wides R., Salzberg S.L., Loftus B., Yandell M., MajorosW.H., Rusch D.B., Lai Z., Kraft C.L., Abril J.F., AnthouardV., Arensburger P., Atkinson P.W., Baden H., de BerardinisV., Baldwin D., and Benes V., et al. 2002. The genome se-
Page 6 and 7: ForewordIn 2001, as we considered t
Page 8: The Finished Genome Sequence of Hom
Page 11 and 12: 4 ROGERSFigure 2. Accumulation of h
Page 13 and 14: 6 ROGERSFigure 4. Sequencing center
Page 15 and 16: 8 ROGERSabcFigure 5. Ensembl view o
Page 17 and 18: 10 ROGERS2000. Analysis of vertebra
Page 20 and 21: The Human Genome: Genes, Pseudogene
Page 22 and 23: VARIATION ON CHROMOSOME 7 15rived f
Page 24 and 25: VARIATION ON CHROMOSOME 7 17DNAs an
Page 26 and 27: VARIATION ON CHROMOSOME 7 19expecte
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Page 30 and 31: Mutational Profiling in the Human G
Page 32 and 33: HUMAN MUTATIONAL PROFILING 25Anothe
Page 34 and 35: HUMAN MUTATIONAL PROFILING 27Figure
Page 36: HUMAN MUTATIONAL PROFILING 29Rieder
Page 39 and 40: 32 SCHMUTZ ET AL.algorithm itself,
Page 41: 34 SCHMUTZ ET AL.Figure 2. Genomic
Page 46 and 47: Human Subtelomeric DNAH. RIETHMAN,
Page 48 and 49: HUMAN SUBTELOMERIC SEQUENCES 41The
Page 50 and 51: HUMAN SUBTELOMERIC SEQUENCES 43cate
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Page 57 and 58: 50 COLLINSand expand the genomics r
Page 59 and 60: 52 COLLINSFigure 2. A public-sector
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Page 63 and 64: 56 BENTLEYmon over many generations
Page 65 and 66: 58 BENTLEYTable 1. Genetic Disease
Page 67 and 68: 60 BENTLEY(Clark et al. 1998; Reich
Page 69 and 70: 62 BENTLEYACKNOWLEDGMENTSThe author
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Page 74: GENETIC ANALYSIS OF DNA POOLS 67gen
Page 77 and 78: 70 FAN ET AL.matrix is then mated t
Page 79 and 80: 72 FAN ET AL.Figure 3. Views of gen
Page 81 and 82: 74 FAN ET AL.including 32 duplicate
Page 83 and 84: 76 FAN ET AL.Figure 7. Allele-speci
Page 85 and 86: 78 FAN ET AL.microsphere-based assa
Page 87 and 88: 80 BERTRANPETIT ET AL.function, may
Page 89 and 90: 82 BERTRANPETIT ET AL.diversity in
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86 BERTRANPETIT ET AL.Figure 1. Dec
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88 BERTRANPETIT ET AL.1999. Populat
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90 WINDEMUTH ET AL.Expression data.
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92 WINDEMUTH ET AL.Table 1. A Summa
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94 WINDEMUTH ET AL.Table 2. Signifi
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96 WINDEMUTH ET AL.Table 3. Summary
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98 WINDEMUTH ET AL.Table 6. List of
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100 WINDEMUTH ET AL.Table 6. (Conti
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102 WINDEMUTH ET AL.Table 6. (Conti
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104 WINDEMUTH ET AL.much of a surpr
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106 WINDEMUTH ET AL.Given our resul
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Genetic Variation and the Control o
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GENETIC CONTROL OF TRANSCRIPTION 11
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GENETIC CONTROL OF TRANSCRIPTION 11
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Genome-wide Detection and Analysis
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RECENT SEGMENTAL DUPLICATIONS 117Fi
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RECENT SEGMENTAL DUPLICATIONS 119St
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RECENT SEGMENTAL DUPLICATIONS 121Co
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RECENT SEGMENTAL DUPLICATIONS 123Ho
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The Effects of Evolutionary Distanc
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EVOLUTIONARY DISTANCE AND GENE PRED
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EVOLUTIONARY DISTANCE AND GENE PRED
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Lineage-specific Expansion of KRAB
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EVOLUTION OF ZNF GENES 133Figure 2.
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EVOLUTION OF ZNF GENES 135Figure 4.
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EVOLUTION OF ZNF GENES 137get gene,
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EVOLUTION OF ZNF GENES 139Y., Goodw
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Sequence Organization and Functiona
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CENTROMERE ANNOTATION 143THE CENTRO
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CENTROMERE ANNOTATION 145Figure 4.
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CENTROMERE ANNOTATION 147CONCLUSION
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CENTROMERE ANNOTATION 149Schueler M
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152 PARKHILL AND THOMSONFigure 1. T
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154 PARKHILL AND THOMSONshow very h
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156 PARKHILL AND THOMSONGene Loss a
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158 PARKHILL AND THOMSONYersinia ad
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160 MCKAY ET AL.Choosing Candidate
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162 MCKAY ET AL.new comparative too
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164 MCKAY ET AL.rich. Based on a th
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166 MCKAY ET AL.Embryonic Muscle an
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168 MCKAY ET AL.native polyadenylat
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Building Comparative Maps Using 1.5
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HUMAN CHROMOSOME 1p IN THE DOG 1731
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HUMAN CHROMOSOME 1p IN THE DOG 175(
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HUMAN CHROMOSOME 1p IN THE DOG 177l
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180 GEORGES AND ANDERSSON5. There i
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182 GEORGES AND ANDERSSONplied to r
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184 GEORGES AND ANDERSSONbe common
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186 GEORGES AND ANDERSSONin humans
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Evolving Methods for the Assembly o
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ASSEMBLING LARGE GENOMES 191Figure
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ASSEMBLING LARGE GENOMES 193tant ad
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Mouse Genome Encyclopedia ProjectY.
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MOUSE GENOME ENCYCLOPEDIA PROJECT 1
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DNA Sequence Assembly and Multiple
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EULERIAN ASSEMBLY AND MULTIPLE ALIG
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Ensembl: A Genome InfrastructureE.
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ENSEMBL 215projects often submit th
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218 ZHANGthe majority of these are
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220 ZHANGFigure 2. Demonstration of
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222 ZHANG(G.X. Chen et al., in prep
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224 ZHANGWe are waiting for experim
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Ontologies for Biologists: A Commun
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ONTOLOGIES FOR BIOLOGISTS 229al. 20
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ONTOLOGIES FOR BIOLOGISTS 231TOPIC
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ONTOLOGIES FOR BIOLOGISTS 233a.b.Fi
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ONTOLOGIES FOR BIOLOGISTS 2352003.
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238 JOSHI-TOPE ET AL.Figure 1. The
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240 JOSHI-TOPE ET AL.state of knowl
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242 JOSHI-TOPE ET AL.and co-immunop
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The Share of Human Genomic DNA unde
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DNA UNDER SELECTION FROM HUMAN-MOUS
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Detecting Highly Conserved Regions
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DETECTING MULTISPECIES CONSERVED SE
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266 ROE ET AL.noncoding regions. On
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268 ROE ET AL.a48 hpf embryos in Mi
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270 ROE ET AL.aNovel gene KIAA0819[
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272 ROE ET AL.aMouseRatAP00354.2 Hu
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274 ROE ET AL.Tautz D. and Pfeifle
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276 JAILLON ET AL.Detection of Evol
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278 JAILLON ET AL.Table 1. Distribu
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280 JAILLON ET AL.Table 3. Distribu
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282 JAILLON ET AL.ecotig is a resul
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284 OVCHARENKO AND LOOTSdivergent r
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286 OVCHARENKO AND LOOTSmodulation
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288 OVCHARENKO AND LOOTSsequencing
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290 OVCHARENKO AND LOOTSments of cl
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Evolution of Eukaryotic Gene Repert
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EVOLUTION OF EUKARYOTIC GENES AND I
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304 PENNACCHIO, BAROUKH, AND RUBINA
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306 PENNACCHIO, BAROUKH, AND RUBINh
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308 PENNACCHIO, BAROUKH, AND RUBINA
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High-Throughput Mouse Knockouts Pro
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314 FRIDDLE ET AL.screen to lines o
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Identification of Novel Functional
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100 bp ladder68G1168G1168H1168H6100
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FUNCTIONAL ELEMENTS IN HUMAN DNA 32
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High-resolution Human Genome Scanni
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HUMAN GENOME SCANNING 325false-posi
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HUMAN GENOME SCANNING 327affecting
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HUMAN GENOME SCANNING 329methods fo
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332 MALEK ET AL.Figure 1. The bacte
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334 MALEK ET AL.J., Vincent S., and
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336 HARDISON ET AL.reflect blocks o
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338 HARDISON ET AL.plain the region
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340 HARDISON ET AL.CALIBRATION OF T
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342 HARDISON ET AL.PositionRP2.3noE
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344 HARDISON ET AL.cific chromosoma
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346 WESTON ET AL.these differences
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348 WESTON ET AL.els controlled by
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350 WESTON ET AL.ures prominently i
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352 WESTON ET AL.nal and Bop, which
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354 WESTON ET AL.ablp 1466 bopbcrtB
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356 WESTON ET AL.like fold (Fig. 6)
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Implications of Genomics for Public
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GENETIC EPIDEMIOLOGY 361lytic epide
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GENETIC EPIDEMIOLOGY 363curate risk
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A Model System for Identifying Gene
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PTC TASTE GENETICS 367Figure 2. Hap
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PTC TASTE GENETICS 369Table 2. Hapl
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PTC TASTE GENETICS 371the emergence
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374 MCCALLION ET AL.Figure 1. Schem
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376 MCCALLION ET AL.lier (Carrasqui
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378 MCCALLION ET AL.Table 3. HSCR A
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380 MCCALLION ET AL.Figure 3. Trans
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Genetics of Schizophrenia and Bipol
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SCHIZOPHRENIA AND BIPOLAR AFFECTIVE
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The Genetics of Common Diseases: 10
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GENETICS OF COMMON DISEASES 397with
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GENETICS OF COMMON DISEASES 399SELE
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GENETICS OF COMMON DISEASES 401F.,
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404 CHEUNG ET AL.netic analysis. Ex
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406 CHEUNG ET AL.Figure 3. The expr
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Regulation of α-Synuclein Expressi
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α-SYNUCLEIN EXPRESSION AND PD 411T
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1. The levels of α-synuclein prote
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α-SYNUCLEIN EXPRESSION AND PD 415g
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418 BOTSTEINFigure 1. (A) Blectron
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420 BOTSTEINFigure 3. Cluster diagr
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422 BOTSTEINFigure 6. Kaplan-Meier
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424 BOTSTEINGarber M.E., Troyanskay
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426 ANTONARAKIS ET AL.1316192225283
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428 ANTONARAKIS ET AL.Figure 5. Sam
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430 ANTONARAKIS ET AL.POPULATION VA
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432 JORGENSEN ET AL.tive small mole
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434 JORGENSEN ET AL.FLAG-tagged pro
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436 JORGENSEN ET AL.visualization t
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438 JORGENSEN ET AL.AArp2/3 Complex
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Pathway40S440 JORGENSEN ET AL.ANutr
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442 JORGENSEN ET AL.Giaever G., Chu
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Genomic Disorders: Genome Architect
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GENOME ARCHITECTURE AND GENOMIC DIS
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Human Versus Chimpanzee Chromosome-
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HUMAN VS. CHIMP CHROMOSOME COMPARIS
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HUMAN VS. CHIMP CHROMOSOME COMPARIS
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Novel Transcriptional Units and Unc
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TRANSCRIPTIONAL UNITS AND GENE PAIR
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mtDNA Variation, Climatic Adaptatio
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mtDNA VARIATION 473Figure 3. Region
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ANALYSIS OF ADAPTIVE SELECTION FORR
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mtDNA VARIATION 477Figure 8. Temper
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Positive Selection in the Human Gen
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HUMAN-SPECIFIC EVOLUTIONARY CHANGES
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488 UNDERHILLorigin episodes, each
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490 UNDERHILLhaplogroups C through
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492 UNDERHILLO (Fig. 2e) that share
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The New Quantitative BiologyM.V. OL
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NEW QUANTITATIVE BIOLOGY 497alone.
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NEW QUANTITATIVE BIOLOGY 499There w
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NEW QUANTITATIVE BIOLOGY 501ceded,
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